{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:08:10Z","timestamp":1768522090233,"version":"3.49.0"},"posted":{"date-parts":[[2025,6,7]]},"group-title":"Cancer Biology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T00:00:00Z","timestamp":1749254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Veteran\u2019s Administration VA Merit Review","award":["I BX001792"],"award-info":[{"award-number":["I BX001792"]}]},{"name":"Research Career Scientist Award","award":["IK6BX004603"],"award-info":[{"award-number":["IK6BX004603"]}]},{"name":"NIH\/NCI","award":["P01 CA171983"],"award-info":[{"award-number":["P01 CA171983"]}]},{"name":"NIH\/NCI","award":["P30 CA044579"],"award-info":[{"award-number":["P30 CA044579"]}]},{"name":"NIH\/NCI","award":["F31 CA271809"],"award-info":[{"award-number":["F31 CA271809"]}]},{"name":"NIH\/NCI","award":["F99 CA284252"],"award-info":[{"award-number":["F99 CA284252"]}]},{"name":"NIH\/NIAID","award":["R01 AI139072"],"award-info":[{"award-number":["R01 AI139072"]}]},{"name":"UVA","award":["Robert R. Wagner Fellowship"],"award-info":[{"award-number":["Robert R. Wagner Fellowship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Resistance to combination regimens containing the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively utilized agent. We previously established the anti-leukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supported leukemic survival and resistance to BH3 mimetics. Here, we report the anti-leukemic efficacy and mechanisms of co-targeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML dataset revealed a positive relationship between increased AC gene expression and venetoclax resistance. Targeting AC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was equipotent to the combination of venetoclax + cytarabine at reducing cell viability when evaluated\n                  <jats:italic>ex vivo<\/jats:italic>\n                  across a cohort of 71 primary AML patient samples. Mechanistically, SACLAC + venetoclax increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Collectively, these data demonstrate the efficacy of co-targeting AC and BCL-2 in AML and rationalize targeting AC as a therapeutic approach to overcome venetoclax resistance.\n                <\/jats:p>","DOI":"10.1101\/2025.06.06.657881","type":"posted-content","created":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T12:10:16Z","timestamp":1749298216000},"source":"Crossref","is-referenced-by-count":0,"title":["Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response"],"prefix":"10.64898","author":[{"given":"Johnson","family":"Ung","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su-Fern","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy J.P.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maansi","family":"Taori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tess M.","family":"Deddens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovana da Costa","family":"Venancio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"McLane M.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James T.","family":"Hagen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raphael T.","family":"Aruleba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Upendar R.","family":"Golla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arati","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. 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